Oxycodone is a well know narcotic employed for pain management. Page 1245 of the thirteenth edition of the Merck Index states that oxycodone may be prepared “ . . . by catalytic reduction of hydroxycodeinone, its oxime, or its bromination products or by reduction of hydoxycodeinone with sodium hydrosulfite.”
The prior art describes several methods for oxycodone using codeine or a salt thereof as the starting material. Codeine along with morphine, thebaine and oripavine may be extracted from poppy straw—see U.S. Pat. No. 6,067,749 issued May 30, 2000 to Fist et al Codeine is also readily prepared by the methylation of morphine, which is present in poppy straw in a higher percentage than that of codeine.
U.S. Pat. No. 6,177,567 B1 issued Jun. 23, 2001 to Chiu et al. discloses a method for the preparation of oxycodone and salts thereof which involves the oxidation of codeine to codeinone, formation of a dienolsilyl ether congener of codeinone in strong amine base, oxidation of the dienolsilyl ether congener using peracetic acid and hydrogenation of the 14-hydroxycodeinone product.
In an article by Ivor Brown and M. Martin-Smith appearing on pp. 4139-4140 of the Journal of The Chemical Society (October, 1960), the authors disclose several methods for the oxidation of codeine to 14-hydroxycodeinone (which may then be reduced to oxycodone) involving the use of oxidants such as manganese dioxide or chromic oxide in acetic acid.
U.S. Pat. No. 6,008,355 issued Dec. 28, 1999 to Huang et al. discloses two methods for preparing oxycodone from codeine. The first method involves oxidizing codeine so as to form codeinone and thereafter converting the codeinone to oxycodone in a two-step, one-pot reaction involving the reaction of codeinone with hydrogen peroxide in water in the presence of an acid at about 15 to about 70° C. to form 14-hydroxycodeinone and then catalytically hydrogenating 14-hydroxycodeinone in its original reaction mixture to form oxycodone.
The second method disclosed in the '355 patent involves oxidizing codeine so as to form codeinone, reacting codeinone with an acylating agent in water or a solubilizing solvent mixture in the presence of an acid at about 15 to about 70° C. to form acyldienolate, oxidizing the dienolate to 14-hydroxycodeinone and then catalytically hydrogenating 14-hydroxycodeinone in its original reaction mixture to form oxycodone.
All of the prior art methods for preparing oxycodone from codeine or a salt thereof are disadvantageous from a commercial manufacturing point of view in several respects: The purity of the oxycodone is relatively low, thereby requiring considerable additional costly purification steps (and attendant loss of yield) to raise the purity to an acceptable level. A second disadvantage of prior art methods is that they require the use of expensive reagents and the reactions are very time-consuming and are quite sensitive to reaction conditions. Thirdly, and most importantly, the prior art methods result in poor yields or the oxycodone and therefore such methods are unsuitable for commercial manufacturing operations.